Histone methyltransferases (HMTs), a class of enzymatic “writers” of epigenetic marks, have recently emerged as targets of potential therapeutic value. They catalyze the methylation of histone lysines and arginines utilizing S-adenosyl-methionine (SAM) as the cofactor/methyl-source. This process can result in either the activation or repression of transcription. Dysregulation of methylation at specific histone sites (alterations in the “histone code”) has been implicated in many cancers such as breast cancers, prostate cancers, renal cell carcinoma, and myeloid and lymphoblastic leukaemia (Chi P. et al. (2010) Nat. Rev. Cancer 10, 457-469). Hence, targeting HMT activity has been the subject of much investigation in the field of oncology.
Suppressor of variegation 4-20 homolog 1 (SUV420H1) is a SET domain-containing histone methyltransferase that localizes to heterochromatin (Schotta G. et al. (2004) Genes & development 18: 1251-1262). There are two isoforms of SUV420H1, both of which contain the conserved SET domain but differ at their C-termini, as well as a closely related homolog, SUV420H2 (Tsang L. W. et al. (2010) PloS one 5: e14447). SUV420H1 binds heterochromatin protein 1 (HP1) and this interaction functions to recruit SUV420H1 to heterochromatin. SUV420H1 catalyzes the di-methylation of histone H4 at lysine 20 (H4K20), which mediates a number of biological processes, including DNA replication, DNA damage-induced stress signaling, and the maintenance of pericentric and telomeric heterochromatin (Schotta G. et al. (2004) Genes & development 18: 1251-1262; Benetti R. et al. (2007) The Journal of cell biology 178: 925-936; Schotta G. et al. (2008) Genes & development 22: 2048-2061; Beck D. B. et al. (2012) Genes & development 26: 2580-2589; Kuo A. J. et al. (2012) Nature 484: 115-119; Tuzon C. T. et al. (2014) Cell reports 8: 430-438).
There is an increasing body of evidence indicating SUV420H1 plays a key role in cell growth and proliferation, and may be associated with proliferative diseases such as cancers. SUV420H1 knockout animals show embryonic and perinatal lethality (Schotta G. et al. (2008) Genes & development 22: 2048-2061). Furthermore, SUV420H1-deficient cells show reduced proliferation rates and growth arrest/senescence due to defects in DNA replication during S phase (Schotta G. et al. (2008) Genes & development 22: 2048-2061). Mechanistically, these defects in DNA replication arise from the lack of SUV420H1-dependent H4K20 dimethylation and subsequent inhibition of replication origin licensing (Beck D. B. et al. (2012) Genes & development 26: 2580-2589; Kuo A. J. et al. (2012) Nature 484: 115-119). Indeed, proteins involved in replication origin licensing have been pursued as targets for cancer therapy (Lei M. (2005) Current cancer drug targets 5: 365-380; Zimmerman K. M. et al. (2013) Molecular cancer research: MCR 11: 370-380). SUV420H1 is also important in regulating non-homologous end joining processes during the DNA damage response to double strand breaks (Schotta G. et al. (2008) Genes & development 22: 2048-2061; Tuzon C. T. et al. (2014) Cell reports 8: 430-438). In particular, inhibition of non-homologous end joining processes has been shown to sensitize pancreatic, breast, cervical and colon cancer cells to DNA damaging agents (Zhao Y. et al. (2006) Cancer research 66: 5354-5362; Chen X. et al. (2008) Cancer research 68: 3169-3177; Li Y. H. et al. (2012) PloS one 7: e39588).
Currently no small molecule inhibitors of SUV420H1 have been reported. Accordingly, there is a need for novel compounds able to inhibit SUV420H1.